I. Field of the Invention
The present invention relates generally to a system for transdermal delivery of therapeutic agents using skin-worn iontophoresis devices to introduce such substances into the body. More specifically, this invention provides a method for safe prolonged delivery of drugs that are formulated as hydrochloride salts, particularly including those which are normally skin irritants, such as donepezil HCl, using a skin-worn patch including a sacrificial active metal based electrode system.
II. Related Art
The process of iontophoresis has found commercial use in the delivery of many ionically charged therapeutic agent compounds. In this delivery method, ions bearing a charge are driven across the skin at the site of an electrode of like charge. The application time and level of current flow (usually reported in units of milli-amp minutes) directly correlates to the amount of drug delivered, and the efficiency of drug delivery can be measured by the proportion of current carried by drug molecules, relative to the current carried by competing non-medication ions having the same charge as the medication.
Self-contained, wearable iontophoretic systems have been developed in which the electrical circuitry and power supply have been integrated into a single, skin-worn patch that includes a pair of electrodes in electrical communication with a subject's skin. An important consideration for reliability and function of iontophoretic devices rests in the choice and design of the electrodes used. Electrode materials can be “inert”, remaining unchanged during the passage of current. Examples include platinum, gold, and carbon. Inert electrode materials, however, are associated with the possibility of pH changes at the electrode sites as a result of electrochemical oxidation of water at the anode and reduction of water at the cathode. These reactions occur with current flow and produce acidic changes at the anode and alkaline changes at the cathode which can cause moderate or even severe skin irritation or burns with a skin-worn patch.
The pH changes associated with inert electrode materials can be eliminated by the use of a “sacrificial” electrode materials which are materials that are consumed by an electrochemical reaction during the passage of current. For example, silver chloride in cathodes is reduced to silver during the passage of current. Conversely, sacrificial anodes are oxidized and include materials such as silver, zinc, or other readily oxidizable metals (metals that oxidize in preference to water).
In iontophoresis devices, the sacrificial material content must be at least sufficient to deliver the intended amount of drug and to last for the intended delivery period. To accomplish this, it is desirable that the electrode be designed to continue to function until the sacrificial material of the electrode is completely depleted avoiding any premature break in electrical connection to the electrode during a prolonged delivery period.
Another important factor for consideration with iontophoresis for prolonged delivery periods relates to skin irritation. Compounds that are themselves irritants to skin have heretofore not been suitable for delivery using iontophoretic devices, as these devices require skin contact with these compounds. This is particularly significant in applications designed to deliver such compounds into the skin for prolonged periods (periods of at least 6 hours and up to 7 days or more, for example).